Search results for "Genotoxic Stress"
showing 10 items of 11 documents
CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin
2021
Summary Limited therapeutic options are available for advanced colorectal cancer (CRC). Herein, we report that exposure to a neo-synthetic bis(indolyl)thiazole alkaloid analog, nortopsentin 234 (NORA234), leads to an initial reduction of proliferative and clonogenic potential of CRC sphere cells (CR-CSphCs), followed by an adaptive response selecting the CR-CSphC-resistant compartment. Cells spared by the treatment with NORA234 express high levels of CD44v6, associated with a constitutive activation of Wnt pathway. In CR-CSphC-based organoids, NORA234 causes a genotoxic stress paralleled by G2-M cell cycle arrest and activation of CHK1, driving the DNA damage repair of CR-CSphCs, regardless…
Ras-related GTPase Rhob represses NF-kappaB signaling.
2000
rhoB encoding a Ras-related GTPase is immediate-early inducible by genotoxic treatments, indicating that it is part of the cellular stress response. Here, we investigated the influence of RhoB on signal pathways that are rapidly evoked by genotoxic compounds. The data obtained show that wild-type RhoB neither affects activation of mitogen-activated protein kinases nor AP-1-dependent gene expression. However, RhoB inhibited both basal and genotoxic agent-stimulated activity of the transcription factor nuclear factor kappaB (NF-kappaB). Thus, RhoB attenuated alkylation-induced increase in the DNA binding activity of NF-kappaB and abrogated NF-kappaB-driven gene expression. Furthermore, RhoB i…
Inhibition of Protein Isoprenylation Impairs Rho-Regulated Early Cellular Response to Genotoxic Stress
2000
Activation of c-Jun N-terminal kinases (JNKs) and nuclear factor-kappaB (NF-kappaB) are early cellular responses to genotoxic stress involved in the regulation of gene expression. Pretreatment of cells with the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin blocked stimulation of JNK1 activity by UV irradiation and by treatment with the alkylating compound methyl methanesulfonate but did not affect activation of extracellular signal-regulated kinase 2 by UV light. Lovastatin also attenuated UV-induced degradation of the NF-kappaB inhibitor IkappaBalpha. The effects of lovastatin on UV-triggered stimulation of JNK1 as well as on IkappaBalpha degradation were reverted by cotreatmen…
The yeast mitogen-activated protein kinase Slt2 is involved in the cellular response to genotoxic stress
2012
Abstract Background The maintenance of genomic integrity is essential for cell viability. Complex signalling pathways (DNA integrity checkpoints) mediate the response to genotoxic stresses. Identifying new functions involved in the cellular response to DNA-damage is crucial. The Saccharomyces cerevisiae SLT2 gene encodes a member of the mitogen-activated protein kinase (MAPK) cascade whose main function is the maintenance of the cell wall integrity. However, different observations suggest that SLT2 may also have a role related to DNA metabolism. Results This work consisted in a comprehensive study to connect the Slt2 protein to genome integrity maintenance in response to genotoxic stresses.…
Neuroprotection elicited by P2Y13 receptors against genotoxic stress by inducing DUSP2 expression and MAPK signaling recovery.
2014
AbstractNucleotides activating P2Y13 receptors display neuroprotective actions against different apoptotic stimuli in cerebellar granule neurons. In the present study, P2Y13 neuroprotection was analyzed in conditions of genotoxic stress. Exposure to cisplatin and UV radiation induced caspase-3-dependent apoptotic cell death, and p38 MAPK signaling de-regulation. Pre-treatment with P2Y13 nucleotide agonist, 2methyl-thio-ADP (2MeSADP), restored granule neuron survival and prevented p38 long-lasting activation induced by cytotoxic treatments. Microarray gene expression analysis in 2MeSADP-stimulated cells revealed over-representation of genes related to protein phosphatase activity. Among them…
Rho GTPases Are Involved in the Regulation of NF-κB by Genotoxic Stress
2001
A common cellular response to genotoxic agents and inflammatory cytokines is the activation of NF-kappaB. Here, we addressed the question of whether small GTPases of the Rho family are involved in the stimulation of NF-kappaB signaling by genotoxic agents or TNFalpha in HeLa cells. Inhibition of isoprenylation of Rho proteins by use of the HMG-CoA reductase inhibitor lovastatin attenuated UV-, doxorubicin-, and TNFalpha-induced degradation of IkappaBalpha as well as drug-stimulated DNA binding activity of NF-kappaB. Furthermore, NF-kappaB-regulated gene expression stimulated by either UV irradiation or treatment with TNFalpha was abrogated by lovastatin pretreatment. This indicates that iso…
DNA Damage Response and the Balance Between Cell Survival and Cell Death
2009
DNA damage induces the activation of a cascade of kinases that trigger the DNA damage response (DDR). Downstream are targets that either help cells to survive or undergo cell death. DNA damage-induced cell death is executed by apoptosis, necrosis, mitotic catastrophe, and autophagy. Of these different forms of cell inactivation, apoptosis is often the main route of cell death following DNA damage. Cells undergo apoptosis upon genotoxic stress via the death receptor and/or the intrinsic mitochondrial damage pathway, with p53 and AP-1 involved decisively. Not every type of DNA damage induces apoptosis. Many DNA lesions are tolerated by the cell, some are mutagenic without being toxic and some…
Induction of DNA Repair Genes in Mammalian Cells in Response to Genotoxic Stress
2006
Genotoxic agents provoke the activation of receptor-triggered pathways and DNA damage-related functions. Here we review data on immediate-early cellular responses and transcriptional activation of DNA repair genes following exposure of mammalian cells to genotoxic stress. Functional consequences of induction of DNA repair genes are also briefly discussed.
Rac1 GTPase, a multifunctional player in the regulation of genotoxic stress response
2013
The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the Ras-homologous (Rho) family of small GTPases, which transduce signals from the outside to the inside of a cell. Rac1 becomes activated upon ligand binding of a variety of receptors, including receptor tyrosine kinases and heterotrimeric G-protein-coupled receptors. After GTP loading by guanine exchange factors (GEFs), GTP-bound Rac1 engages numerous effector proteins, thereby eventually regulating cell motility and adhesion, cell cycle progression through G1, mitosis and meiosis, as well as cell death and metastasis.1 Besides, Rac1 adjusts cellular responses to genotoxic agents, such as UV light and alkylating agents, by r…
Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy
2016
AbstractInactivation of p53 found in more than half of human cancers is often associated with increased tumor resistance to anti-cancer therapy. We have previously shown that overexpression of the phosphatase Wip1 in p53-negative tumors sensitizes them to chemotherapeutic agents, while protecting normal tissues from the side effects of anti-cancer treatment. In this study, we decided to search for kinases that prevent Wip1-mediated sensitization of cancer cells, thereby interfering with efficacy of genotoxic anti-cancer drugs. To this end, we performed a flow cytometry-based screening in order to identify kinases that regulated the levels of γH2AX, which were used as readout. Another criter…